Discovery of a Proneurogenic, Neuroprotective Chemical

Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA.
Cell (Impact Factor: 32.24). 07/2010; 142(1):39-51. DOI: 10.1016/j.cell.2010.06.018
Source: PubMed


An in vivo screen was performed in search of chemicals capable of enhancing neuron formation in the hippocampus of adult mice. Eight of 1000 small molecules tested enhanced neuron formation in the subgranular zone of the dentate gyrus. Among these was an aminopropyl carbazole, designated P7C3, endowed with favorable pharmacological properties. In vivo studies gave evidence that P7C3 exerts its proneurogenic activity by protecting newborn neurons from apoptosis. Mice missing the gene encoding neuronal PAS domain protein 3 (NPAS3) are devoid of hippocampal neurogenesis and display malformation and electrophysiological dysfunction of the dentate gyrus. Prolonged administration of P7C3 to npas3(-/-) mice corrected these deficits by normalizing levels of apoptosis of newborn hippocampal neurons. Prolonged administration of P7C3 to aged rats also enhanced neurogenesis in the dentate gyrus, impeded neuron death, and preserved cognitive capacity as a function of terminal aging. PAPERCLIP:

Download full-text


Available from: Noelle S Williams,
54 Reads
  • Source
    • "Isx-9 also has therapeutic promise as it can induce terminally differentiated astrocytes to re-express neuronal genes and regain neurogenic potential in vitro (Zhang et al. 2011), revealing another way to recruit progenitor cells available for neuronal differentiation. Different small molecules also target different stages of neurogenesis; for example, KHS101 accelerates neuronal differentiation (Wurdak et al. 2010), and P7C3, prevents apoptosis of newborn neurons and improves cognition in aged rats (Pieper et al. 2010). Additional high throughput screening assays will likely lead to the discovery of additional neurogenic molecules and elucidate novel mechanisms regulating neurogenesis in healthy and pathological brain states. "
    [Show abstract] [Hide abstract]
    ABSTRACT: With the growth of the aging population and increasing life expectancy, the diagnosis of age-related neurodegenerative diseases is predicted to increase 12% by 2030. There is urgent need to develop better and novel treatments for disorders like Alzheimer's, Huntington's, and Parkinson's diseases. As these neurodegenerative diseases are customarily defined by the progressive loss of neurons, treatment strategies have traditionally focused on replacing neurons lost during disease progression. To this end, the self-renewing and multipotent properties of neural stem/precursor cells (NSPCs) that exist in the adult brain suggest that NSPCs could contribute to a therapy for replacement of damaged or lost neurons. Although a wealth of research demonstrates the proof-of-concept that NSPC transplantation has therapeutic potential, there are considerable barriers between the theory of cell transplantation and clinical implementation. However, a new view on harnessing the power of NSPC for treatment of neurodegenerative disorders has emerged, and focuses on treating neuropathological aspects of the disease prior to the appearance of overt neuronal loss. For example, rather than merely replacing lost neurons, NSPCs are now being considered for their ability to provide trophic support. Here we review the evolution of how the field has considered application of NSPCs for treatment of neurodegeneration disorders. We discuss the challenges posed by the "traditional" view of neurodegeneration - overt cell loss - for utilization of NSPCs for treatment of these disorders. We also review the emergence of an alternative strategy that involves fine-tuning the neurogenic capacity of existing adult NSPCs so that they are engineered to address disease-specific pathologies at specific time points during the trajectory of disease. We conclude with our opinion that for this strategy to become a translational reality, it requires a thorough understanding of NSPCs, the dynamic process of adult neurogenesis, and a better understanding of the pathological trajectory of each neurodegenerative disease.
    03/2015; 1(3):335-351.
  • Source
    • "Once activated, microglia proliferate rapidly and secrete pro-inflammatory cytokines, chemokines, and neurotoxic molecules that contribute to a toxic microenvironment leading to neuronal death (Beggs and Salter, 2007; Block et al., 2007; Benarroch, 2013). P7C3 has been shown to foster stabilization of mitochondrial membrane potential in the face of otherwise overwhelming toxic insult (Pieper et al., 2010),and P7C3 may be acting directly on neurons in our model. In our model, neuronal Fig. 6. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Nerve injuries cause pain, paralysis and numbness that can lead to major disability, and newborns often sustain nerve injuries during delivery that result in lifelong impairment. Without a pharmacologic agent to enhance functional recovery from these injuries, clinicians rely solely on surgery and rehabilitation to treat patients. Unfortunately, patient outcomes remain poor despite application of the most advanced microsurgical and rehabilitative techniques. We hypothesized that the detrimental effects of traumatic neonatal nerve injury could be mitigated with pharmacologic neuroprotection, and tested whether the novel neuroprotective agent P7C3 would block peripheral neuron cell death and enhance functional recovery in a neonatal nerve injury model. Administration of P7C3 after sciatic nerve crush injury doubled motor and sensory neuron survival, and also promoted axon regeneration in a dose-dependent manner. Treatment with P7C3 also enhanced behavioral and muscle functional recovery, and reversed pathological mobilization of spinal microglia after injury. Our findings suggest that the P7C3 family of neuroprotective compounds may provide a basis for the development of a new neuroprotective drug to enhance recovery following peripheral nerve injury.
    Neuroscience 10/2014; 284. DOI:10.1016/j.neuroscience.2014.10.005 · 3.36 Impact Factor
  • Source
    • "Interestingly, mice lacking Npas3, a genetic risk factor for schizophrenia, have SGZ proliferation deficits that accompany a thinning of the dentate gyrus and a loss of dendritic complexity in the mature neurons extending processes into the molecular layer and CA3 [29], [30]. While Disc131L/31L mutants have proliferation deficits and a degree of dentate gyrus thinning (though not reaching statistical significance) consistent with Npas3 null mice, only Disc1100P/100P mice have similar changes in neuronal morphology. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Disrupted in schizophrenia 1 (DISC1) is a risk factor for a spectrum of neuropsychiatric illnesses including schizophrenia, bipolar disorder, and major depressive disorder. Here we use two missense Disc1 mouse mutants, described previously with distinct behavioural phenotypes, to demonstrate that Disc1 variation exerts differing effects on the formation of newly generated neurons in the adult hippocampus. Disc1 mice carrying a homozygous Q31L mutation, and displaying depressive-like phenotypes, have fewer proliferating cells while Disc1 mice with a homozygous L100P mutation that induces schizophrenia-like phenotypes, show changes in the generation, placement and maturation of newly generated neurons in the hippocampal dentate gyrus. Our results demonstrate Disc1 allele specific effects in the adult hippocampus, and suggest that the divergence in behavioural phenotypes may in part stem from changes in specific cell populations in the brain.
    PLoS ONE 10/2014; 9(10):e108088. DOI:10.1371/journal.pone.0108088 · 3.23 Impact Factor
Show more